Melanoma Combination Granted Priority Review Designation by FDA

Published Online: October 22, 2013

Christina Izzo

Last month, the US Food and Drug Administration (FDA) granted Priority Review to dabrafenib (Tafinlar) and trametinib (Mekinist) as a combination treatment for patients with unresectable or metastatic melanoma with a BRAFV600E/K mutation.

According to a September 16 statement from the drugs’ manufacturer, GlaxoSmithKline, the FDA has set target dates in early January 2014 to review the trametinib and dabrafenib supplements. The drugs were approved simultaneously as single agents earlier this year.

Each drug treats melanoma through a different mechanism of action. Dabrafenib is a BRAF inhibitor approved to treat patients who express the BRAFV600E mutation, while trametinib, a MEK 1/2 inhibitor, is approved to treat patients with either the BRAFV600E or BRAFV600K mutation. Both drugs act on the RAS kinase pathway, dabrafenib at an earlier point than trametinib. A patient will typically develop resistance to dabrafenib monotherapy after about 5 to 7 months. The addition of trametinib helps overcome the tumor’s resistance mechanism, allowing for a more durable response to treatment.

The Priority Review was granted based on the results of a randomized phase I/II study that compared combination therapy with dabrafenib and trametinib with dabrafenib monotherapy in adult patients with BRAFV600E/K mutation-positive metastatic melanoma. According to the study that was published in the New England Journal of Medicine, progression-free survival (PFS), response rate, and duration of response favored the combination of dabrafenib and trametinib compared with single agent dabrafenib for patients with BRAFV600E/K–positive metastatic melanoma.1

The phase II study randomized 162 patients with BRAFV600E/K–positive metastatic melanoma to 1 of 3 treatment arms: monotherapy with dabrafenib at 150 mg/BID; combination of dabrafenib at 150 mg/BID plus 1 mg of once-daily trametinib; or concurrent full doses of both drugs (dabrafenib at 150 mg/BID; once-daily trametinib at 2 mg). The median PFS for patients who received the full-dose combination was 9.4 months, as compared with 5.8 months with dabrafenib monotherapy (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P <.001).

Side effects associated with MEK inhibitors, including peripheral edema, hypertension, decreased cardiac ejection fraction, and ocular events, had a higher occurrence in the combination therapy, while side effects associated with BRAF inhibitors of hyperproliferative skin lesions occurred less frequently in the combination group compared with the monotherapy group.

In February 2013, the global phase III COMBI-AD study began, aiming to analyze the combination of dabrafenib and trametinib as adjuvant therapy for patients with melanoma.

The study will evaluate whether the combination of agents can delay or prevent the recurrence of melanoma (Relapse Free Survival) in patients with Stage IIIa, IIIb, or IIIc BRAFV600E/K mutation-positive melanoma that has been completely removed by surgery. The study will also evaluate the safety profile of the dabrafenib-trametinib combination in this treatment setting. “The patients included in this trial are at high risk of their melanoma returning after surgery and there are currently few treatment options to reduce this risk,” Rafael Amado, MD, head of Oncology Research and Development for GlaxoSmithKline, said in a statement when the trial was announced.

“Given the efficacy and safety findings observed with combined dabrafenibtrametinib treatment in the metastatic setting, we are investigating whether the combination administered after surgery can help these patients live longer without melanoma recurrence.” There are 2 additional phase III studies ongoing, aimed to evaluate the combination of dabrafenib and trametinib for patients with metastatic BRAFV600 melanoma.